Posttranscriptional Derepression of GADD45α by Genotoxic Stress

Abstract

The growth arrest- and DNA damage-inducible gene GADD45alpha is potently upregulated in response to stress stimuli. Here, two RNA binding proteins, the mRNA decay-promoting AUF1 and the translational suppressor TIAR, were found to interact specifically with the 3' untranslated region (UTR) of the GADD45alpha mRNA in HeLa cells. These associations were prominent in unstimulated cells, decreasing dramatically after treatment with the genotoxin methyl methanesulfonate (MMS). Analysis of both endogenous and chimeric GADD45alpha mRNA revealed that in untreated cells AUF1 strongly reduced GADD45alpha mRNA stability, whereas TIAR potently inhibited GADD45alpha translation. After genotoxic stress, AUF1 and TIAR dissociated from the GADD45alpha mRNA, thereby allowing coordinated elevations in both GADD45alpha mRNA half-life and translation rate, respectively. We propose that the posttranscriptional derepression of GADD45alpha critically contributes to its potent upregulation after DNA damage.

RNA-binding proteins regulate cell respiration and coenzyme Q biosynthesis by post-transcriptional regulation ofCOQ7

“…57,58 HuR and hnRNP C1/C2 are predominantly located in the nucleus, but these proteins can shuttle between the nucleus and the cytoplasm in different cellular conditions, such as oxidative stress, UV radiation exposure or genotoxic stress. [59][60][61][62] The relation of HuR with mitochondria is described throughout its association with b-F1-ATPase mRNA 63 and the regulation of antiapoptotic proteins such as Bcl2 or BCL xL , 64,65 and here we show the direct interaction of both HuR and hnRNP C1/C2 to COQ7 mRNA, the key enzyme of CoQ biosynthesis pathway.…”

RNA-binding protein nucleolin in disease

“…45 Interestingly, GADD45A mRNA is also a target of the translational suppressor TIAR and the decay-promoting protein AUF1, two RBPs that dissociate after treatment with the alkylating agent methyl methanesulfonate (MMS). 44 These findings suggest a functional interplay between nucleolin, TIAR and AUF1 to promote the expression of Gadd45α under stress conditions. decade has uncovered many other functions linked to the binding of nucleolin to mRNAs (Fig.…”

“…The growth arrest-and DNA damageinducible 45 protein (Gadd45α) is induced under stress conditions. 44 The stress agent arsenite enhances the association of nucleolin with GADD45A mRNA, leading to transcript stabilization. 45 Interestingly, GADD45A mRNA is also a target of the translational suppressor TIAR and the decay-promoting protein AUF1, two RBPs that dissociate after treatment with the alkylating agent methyl methanesulfonate (MMS).…”

mRNA stability control: a clandestine force in normal and malignant hematopoiesis

“…The 3 0 -UTR is a composite structure of multiple regulatory elements that may respond in a coordinated fashion to a single stimulus, 43 or might each respond to a different stimulus. The 3 0 -UTR of the p21 gene, for instance, contains an ARE that promotes p21 turnover but is bound by stabilizing proteins to increase p21 mRNA half-life in response to a-1 agonists, 44 prostaglandin A1, 45 ultraviolet light 46 and mediators of muscle 47 or neuronal differentiation.…”

“…114 Knockdown experiments targeting all four AUF1 isoforms have confirmed the destabilizing effects of AUF1 against multiple ARE-containing transcripts. 43,108,[120][121][122] Although many reports demonstrate a destabilizing effect of AUF1 on mRNA transcripts, some studies indicated that it can also have a stabilizing effect. Overexpression of each of the four AUF1 isoforms stabilized a b-globin construct containing a GM-CSF or c-fos ARE.…”